Trials in the first-line therapy* for people with stage IV metastatic colorectal cancer (mCRC).

For this month’s Clinical Trials Conversations, we’re diving into trials in the first-line therapy* for people with stage IV metastatic colorectal cancer (mCRC). *First-line therapy is defined as the first-therapy given after a diagnosis of colorectal cancer. In this blog, we’re exploring first line therapy specifically for patients with mCRC.

Maia, can you tell us about a few clinical trials for patients who are about to receive first-line therapy for their metastatic CRC that we should be talking about?

The first trial I’d like to highlight is NCT03953235: “Neoantigen-based therapeutic cancer vaccine, in combination with immune checkpoint blockade (GO-005).”

This clinical trial, ongoing at several locations nationwide, recruits microsatellite stability (MSS) CRC patients who are receiving first-line (1L) therapy for mCRC and also those who received that firstline for mCRC and progressed on it, but who have not received the following line. 

In this trial, patients with certain mutations receive a combination of two or three immunotherapies: a prime/boost therapeutic vaccine (called GRT-C903/GRT-R904), which targets shared neoantigens; an anti PD-1 (checkpoint inhibitor Nivolumab); and, in some cases, an anti-CTLA-4 (checkpoint inhibitor Ipilimumab). 

The targeted mutations are:

  • BRAF_G466V
  • CTNNB1_S37F 
  • CTNNB1_S45F 
  • CTNNB1_S45P 
  • CTNNB1_T41A 
  • ERBB2_Y772_A775dup 
  • KRAS_G12C or NRAS_G12C 
  • KRAS_G12D or NRAS_G12D 
  • KRAS_G12V / KRAS_G13D 
  • KRAS_Q61H or NRAS_Q61H 
  • KRAS_Q61K or NRAS_Q61K 
  • KRAS_Q61L or NRAS_Q61L 
  • KRAS_Q61R or NRAS_Q61R 
  • TP53_K132E 
  • TP53_K132N 
  • TP53_R213L 
  • TP53_R249M 
  • TP53_S127Y

Neoantigens are small protein fragments that arise as the result of the mutations found in the DNA of tumor cells. They are not found in normal cells. These new ("neo") antigens look foreign to the T cells, so they can potentially elicit very potent responses if the T cells consider them dangerous. Shared neoantigens are those new, mutated antigens that are known or expected to be common across a subset of patients.

A vaccine targeting these neoantigens aims to use them to activate the body’s anti-tumor immune response to eliminate cancer cells.

For more details (about design, eligibility, locations, etc.), check the clinical trial record and preliminary report from this trial

The next trial I’d like to highlight is NCT04714983: * Intra-tumoral (liver lesions) injections of oncolytic adenovirus called DNX-24.

Several clinical trials are investigating the *addition* of immunotherapy, perioperatively (before or after surgery), with the idea of re-engaging the immune system itself to prevent recurrence.

Too often, patients are not aware of these options because of incorrect ideas about clinical trials (“clinical trials are a last resource";  “they are always alternative to standard of care” —instead of a complement, sometimes). Also, it’s unlikely that patients know such trials exist when the studies are not offered at the facility where they are being treated.

Be sure to check out common clinical trial misconceptions!

A stage IV patient who is aiming for a liver resection with curative intent may want to consider options to prevent recurrence, which sometimes happens despite prior and/or "mop up" chemotherapy offered by standard of care. 

One of such trials is a small one (at Moffitt Cancer Center in Tampa, Fla.). It administers an experimental immunotherapy (an oncolytic virus: a “virus that destroys cancer”), in the form of two injections given directly into the liver tumors before surgery. That is: It is for patients who are just receiving first-line (1L) therapy for the metastatic setting.

"The purpose of this study is to test an experimental oncolytic adenovirus called DNX-2440 in patients with resectable multifocal (≥ 2 lesions) liver metastasis, who are scheduled to have curative-intent liver resection surgery.” Patients will receive two consecutive intra-tumoral (meaning within the tumor) injections of DNX-2440 into a metastatic liver lesion prior to surgery for liver resection. The agent was developed by researchers at MD Anderson Cancer Center in Houston, Texas, and is also in trials for a difficult to treat brain cancer (glioblastoma). Learn more about this trial.

That’s very insightful, Maia. Manju, what trials do you think are interesting for our community to learn about?

The first is BREAKWATER for those with a BRAF V600e mutation and who have mCRC.This international trial with over 77 locations is to find out whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes compared to current standard of care (SOC) chemotherapy in patients with BRAF V600E-mutant mCRC who have not started any treatment yet. Though the BEACON doublet combination (encorafenib —a BRAF inhibitor— and cetuximab —an antibody targeting EGFR) works well for a large number of patients with a BRAF V600e mutated tumors, sooner or later resistance clones (these are groups of tumor cells with other molecular alterations that may arise/get selected as a result of treatment and render the treatment ineffective) develop and the treatment may stop working. 

This trial is an effort to find out if adding chemotherapy to the BEACON doublet can delay the occurrence of resistance clones. 

The trial has a 60 patient safety lead-in to look at the safety and tolerability of combining chemotherapy with targeted therapy. As I understand, safety lead-in are initial cohorts of a study to figure out the safety and tolerability of new drugs/combinations being tested before large sets of patients are randomized to the trial arms. The next part of the trial usually uses the information from the safety lead-in to inform that part of the trial. In this safety lead-in, there are two cohorts 1) EC+Folfiri and 2) EC+Folfox. This will help identify the targeted therapy+chemo combination that will be used in the second part of the trial. Once 30 evaluable patients are enrolled in each cohort and complete cycle one, several parameters will be examined.  I have heard this part is done enrolling.

The trial has 930 participants and three arms:

  1. EC alone (targeted therapy alone)
  2. EC+Folfiri or EC+Folfox (targeted therapy+chemo)
  3. Folfox+Bev or Folfiri+Bev or Folfoxiri+Bev or Capox+Bev (SOC Chemo+biological arm)

I am really looking forward to the results from the safety lead-in. Trials for BRAF mutated CRC are much needed as this is a very aggressive form of the disease, and approaches such as this trial, which combines chemotherapy with targeted therapy may help keep the disease at bay for a longer period of time. If the safety and tolerability of the combination is manageable, perhaps similar approaches can be tried for KRAS mutated CRC as well.

To learn more about clinical trials, be sure to follow our blog series highlighting various trials each month. You can also sign up for Fight CRC’s patient eGuide each month at FightCRC.org.

Stay Tuned for More!

Once a month, Maia and Manju will spend time unpacking important research trials, tips, and advice for our community. Be sure to subscribe to sign up with Fight CRC and join COLONTOWN’s online community to continue receiving the most relevant updates in the CRC world!

You can also follow Maia (@sassycell) and Manju (@manjuggm) to stay updated on research and trials and visit ClinicalTrials.gov for more information on trials.

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